Treating and preventing infectious disease requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. Traditionally, this amounted to a focus on genes of the adaptive immune system. However, equally important are those cellular factors that interact directly with viral macromolecules, either as positive cofactors for virus replication, or as intrinsic host mechanisms for suppressing viral infection. The latter includes the restriction factors - with TRIM5, APOBEC3, BST2/tetherin, SAMHD1, Schlafen-11 and Mx2 being well-studied examples. While individual restriction factors have been extensively studied in isolation (typicall by overexpression in heterologous cell lines), their combined impact at the level of the host organism and the host-population has not been carefully examined. While the antiviral activity of these restriction factors in cell culture is consistent with a role in preventing cross-species transmission of primate lentiviruses in nature, there are little-to-no data that directly support tis hypothesis. In this proposal, we will track the evolution of primate lentiviruses during the earliet stages of adapting to a non-native host (SIVsmm in rhesus macaques) using a combination of next- generation sequencing and bioinformatics tools customized for studying RNA virus populations (AIMS 1 & 3); and establish the biological significance of individual restrictions in terms of the evolutionary consequences of resistance for relative viral fitness (AIM 2).